Perinatal Estrogen Exposure Diethylstilbestrol

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Estrogenic steroids exert regulatory actions on immune function in adult animals that are well documented but not well understood mechanistically. Autoimmune disease may be caused, at least in part, by endogenous estrogen, as has been observed with increased serum estradiol levels (e.g., during pregnancy) and infections resulting from depression of cell-mediated immunity (Hamilton and Hellstrom 1977; Mathur et al. 1979). Pharmacologic or suprapharmacologic levels of steroidal and nonsteroidal estrogenic compounds have been shown to further result in numerous alterations of immune function, particularly when administered perinatally during lym-phoid organ organogenesis. Effects of such administration in rodents include myelotoxicity (Fried et al. 1974; Boorman et al. 1980), suppression of cell-mediated immunity (Kalland et al. 1978; Ways and Bern 1979), significant thymic atrophy (Greenman et al. 1977; Aboussaouira et al. 1991), suppression of natural killer (NK) cell activity (Seaman et al. 1979; Kalland 1980), and reticuloendothelial system stimulation (Kicol et al. 1964; Ford et al. 1983).

DES, a synthetic nonsteroidal compound possessing estrogenic activity, may have possible adverse effects on the postnatal human immune system after in utero exposure in women. As an example, altered NK and T lymphocyte function in women exposed to DES in utero has been reported (Kalland and Fossberg 1981; Ways et al. 1987). In addition, Noller et al. (1988) have demonstrated an increased incidence of autoimmune diseases in women exposed in utero to DES. While it appears that estrogens mediate certain of their immune effects at the thymic level by altering thymic epithelium-dependent mechanisms (Grossman and Roselli 1983), little is understood about mechanisms by which estrogenic chemicals may influence immune responses to foreign or self-antigens.

An increased risk of developing autoimmune disease in mice has been associated with altered prenatal hormonal environment (Walker et al. 1996). It has also been suggested that humans exposed in utero to DES may display a hyperreactive immune response (Anderson et al. 1982). A retrospective study of DES-exposed (1711 individuals) and unexposed (922 individuals) cohorts examined the possibility that prenatal DES may affect the prevalence of autoimmune disease and found a positive correlation when autoimmune diseases were grouped (Noller et al. 1988). Specifically, the overall frequency of any autoimmune disease among exposed women was 28.6 per 1000 compared to 16.3 per 1000 among the controls (significantly different at p=0.02). Autoimmune diseases evaluated included systemic lupus erythematosus, scleroderma, Grave's disease, Hashimoto's thyroiditis, pernicious anemia, myasthenia gravis, thrombocytopenic purpura, rheumatoid arthritis, regional enteritis, chronic ulcerative colitis, multiple sclerosis, chronic lymphocytic thyroiditis, Reiter's syndrome, and optic neuritis. However, only Hashimoto's thyroiditis occurred significantly more often in the exposed women (p=0.04) when these autoimmune diseases were considered individually. A similar evaluation of 1173 humans exposed to DES during development (1079 daughters and 94 sons) found increased rates of asthma, arthritis, and diabetes mellitus compared to the general population (Wingard and Turiel 1988). In a more recent study by Baird et al. (1996) evaluating rates of allergy, infection, and autoimmune disease in DES-exposed sons and daughters (253 men and 296 women) matched with similar unexposed individuals (241 men and 246 women), no differences in disease occurrence were detected. These authors concluded that a larger sample was needed to evaluate DES-associated risk of autoimmunity since autoimmune diseases are relatively rare in the human population.

Data from humans in the preliminary studies above suggest the possibility that exposure to DES in utero may result in postnatal immune alterations, including increased autoimmune disease. However, the difficulty with continued surveillance of DES-exposed sons and daughters required for more definitive statements will become more difficult as this cohort ages and members are lost. This makes laboratory rodent studies important to determine if prenatal exposure to chemicals such as DES may predispose an individual to postnatal autoimmunity via alteration of development of immune cells. Animal models will also be necessary to answer questions regarding specific immune cell targets and mechanisms of action resulting from such exposures.

Hybrid B6C3F1 (C57Bl/6N x C3H) mice exposed to 8 mg/kg/day DES from GD 10 to16 displayed significant thymic hypocellularity in late gestation, as well as limited but significant inhibition of thymocyte maturation (Table 13.1) (Holladay et al. 1993). In these studies, the observed thymic involution was related to a reduction of fetal liver prothymocytes by DES.These fetal liver prothymocytes are responsible for colonizing the fetal thymus. These authors also reported that fetal liver prothymocytes expressed estrogen receptors at about 290 fmol/100 mg DNA, a level approximately 50% of that found in the uterus and sufficient to suggest an estrogen-responsive cell. These and other reports indicate the developing mouse immune system is sensitive to estrogen exposure, and that such exposure may contribute to postnatal immunosuppression (Holladay et al. 1994). However, similar to most of the well-established rodent developmental immunotoxicants, very limited information is available addressing possible relationships between gestational DES exposure and altered expression of postnatal autoimmune disease.

Silverstone et al. reported that a single fetal exposure to DES in SNF1 mice induced autoimmune lupus-like nephritis in male offspring between 5 and 10 months of age (1998). Female SNF1 mice develop this autoimmune syndrome spontaneously

Table 13.1 Fetal Thymocyte CD Surface Marker Expression and Cellularity after DES Treatment

CD Marker Expression DES

Table 13.1 Fetal Thymocyte CD Surface Marker Expression and Cellularity after DES Treatment

CD Marker Expression DES

CD4+8-

4.1

± 0.2

3.2

±

0.4

4.0

±

0.4

CD4-8+

2.7

± 0.2

4.0

±

0.3a

3.3

±

0.3

CD4+8+

71.4

± 0.7

64.0

±

2.5a

63.6

±

1.6a

CD4-8-

22.0

± 0.7

28.8

±

2.5a

29.2

±

1.5a

Cellularity (x 106)

40.4

± 2.6

18.9

±

1.9a

8.7

±

1.9a

Note: CD4 and CD8 surface antigen expression determined in GD 18 fetal mice after maternal exposure to 3 or 8 mg/kg/day DES from GD 10 to 16. Values represent mean ± SEM of 5 mice per treatment group. a p < 0.05 vs. vehicle controls. Source: Modified from Holladay et al. 1993.

in their first year of life. The male mice, however, typically do not display significant autoimmunity before one year of age. These data suggest that pharmacologic exposure to DES may contribute to early expression of autoimmunity in genetically predisposed mice, and that autoimmune rodent models such as the SNF1 model may prove valuable for identification of biological markers for human risk assessment. Because the etiology of autoimmune diseases is generally considered to be multifactorial (genetic, environmental, hormonal, infectious) (Talal 1993), clearly, continued research will be required to determine potential relationships between prenatal estrogen exposure and postnatal development of autoimmune disease.

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